The primary care goal during a heart attack is to quickly restore blood perfusion. Reperfusion, however, is paradoxical, while it enables organ survival; it also enables destructive biochemical processes. While numerous adjunctive therapies for acute myocardial infarctions (AMI) have been studied, innovative combination therapies are needed. Both hypothermia and gradual reperfusion have shown benefit in terms of saving heart tissue following ischemia-reperfusion. The overall goal of this work is to combine these two techniques for additive and perhaps synergistic benefits for improving AMI outcomes. Specific Aims: 1) Develop a combination therapy device that precisely controls reperfusion flow as well as tissue cooling and re-warming. 2) Demonstrate that the proposed combination therapy technology has the ability to carefully and safely control both reperfusion and tissue temperature and provides tissue salvage benefit in a large animal translational ischemia-reperfusion model. To achieve aim #1, a fixed set of design input requirements and feasibility points will be developed, five fully characterized and robust device prototypes will be created ready for in vivo testing, and an optimal operational protocol based on tissue cooling ability and potential efficacy for in vivo testing will be selected. For aim #2, the optimal operational protocl will be tested in a large animal ischemia-reperfusion model. These results will show that the protocol is safe and effective at reducing tissue damage, demonstrating that there is a potential for clinically relevant tissue salvage. Relevance: Approximately 110,000 people each year in the U.S. have an emergency angioplasty procedure. According to the AHA 2010 Statistics, 20% of first time heart attack victims die within one year of the event. FocalCool, LLC's goal is to improve emergency angioplasty patient outcomes by reducing reperfusion injury through safe and effective use of controlled reperfusion hypothermia. If Phase I goals to demonstrate safety, cooling ability, and tissue salvage feasibility of the joint technology are successful, Phase II wok will freeze the design for GLP animal testing and an IDE application and demonstrate efficacy of tissue salvage in a translational preclinical model.